Human African trypanosomiasis (HAT) is a neglected tropical disease (NTD) for which new orally available drugs are needed. As an NTD, funds for discovery of new drugs are limited. Therefore, we have been applying a pragmatic approach of repurposing human kinase inhibitor scaffolds for anti-trypanosome lead discovery. Starting with the FDA-approved drug lapatinib, which killed cultured bloodstream trypanosomes (EC50 = 1600 nM) and had a selectivity index (SI) = 4 (compared to activity against human HepG2 cells), we designed and synthesized over 380 new analogs in a systematic medicinal chemistry campaign. With an eye towards improving SI, toxicity profile, metabolism, physicochemical properties, and CNS availability, our new series includes advanced hits, which are vastly superior to lapatinib in potency (EC50), SI, and aqueous solubility (Aq. Sol.). They include NEU-1060 (EC50 = 6 nM, SI > 2333), NEU-1912 (EC50 = 24 nM, SI > 1458), and NEU-1953 (EC50 = 420 nM, SI > 100, Aq. Sol. = 43 M). By directly comparing NEU-1912 to lapatinib, the following key advances are notable (i) 67-fold EC50 improvement; (ii) over 355-fold SI enhancement; and (iii) a 400% increase in lipophilic ligand efficiency (LLE). NEU-1912, in a proof-of-concept study, prolonged life of trypanosome-infected mice as compared to control (untreated) mice. In initial attempts to fine-tune physicochemical properties of NEU-1912, we have increased solubility 48-fold in NEU-2091, and conferred CNS penetration features with NEU-1060. We propose now to focus our efforts on converting the NEU-1912 chemotype into potential leads, by incorporating substituents that improved physicochemical, metabolic or CNS availability of related analogs. For new leads identified, we will perform mode of action, identify the targets for the leads, and genetically validate their importance for trypanosome proliferation. The overarching goal of our project is to deliver five compounds that meet Lead Criteria for HAT in the next five years. Such compounds will be well-positioned for advancement as preclinical investigational new drugs.